Biology subjects

Fernandez, G.

Publications and source records attributed to Fernandez, G..

At least 19 recordsLinked to original sources

bioRxiv2026

Reproductive experience promotes permanent body growth independently of growth hormone

Pregnancy leads to many adaptations in the maternal body, some of which are reversible. However, reproductive experience can also result in permanent effects. Here, we investigated how pregnancy influences the somatotrophic system and the lasting effects of reproductive experience on the maternal organism. Reproductive experience induced a pronounced increase in lean body mass and longitudinal growth in both wild-type and growth hormone (GH)-deficient mice compared with age-matched virgins. Body growth was primarily observed during the first pregnancy, whereas a second gestation was mostly associated with increased adiposity. Increased GH secretion was observed in pregnant wild-type mice but not in pregnant GHRHR-deficient mice. Pregnancy-induced body growth is preserved despite disruption of GH-, ghrelin-, and estrogen-related signaling pathways. Data from a cohort of women with isolated GH deficiency (IGHD) caused by a loss-of-function mutation in the GHRHR gene revealed that nulliparous women were 7 cm shorter than those with one or more pregnancies. In conclusion, reproductive experience induces permanent changes in the maternal organism, promoting body growth in models that allow this response. Pregnancy-induced body growth appears to be independent of GH action. These findings underscore the need for further studies to investigate the long-lasting consequences of reproductive experience in females.

physiology↗

bioRxiv2026

Associative emotional memory encoding: Insights from network stability analysis of an fMRI-driven bilinear dynamics

The interplay between emotion and memory is a central topic in cognitive neuroscience, with open questions about the underlying neuronal mechanisms. This article studies dynamic interactions among the hippocampus, amygdala, and orbitofrontal cortex during an fMRI associative memory encoding task. Participants were clustered into three condition groups: Neutral-Neutral, Neutral-Emotional, or Emotional-Emotional, and viewed image pairs associated with their assigned condition. Using the dynamic causal modeling framework, we explore several dynamic models and show that a stochastic bilinear state-space model best describes the neuronal dynamics in all conditions. Furthermore, we use graph and control theory techniques to both validate and analyze the model. In particular, we analyze the network dynamics of each condition using tools from graph theory and stability theory and discuss the differences in the strength and direction of connectivity as well as the stability of each of these networks. We confirm the prior finding that memory is enhanced in emotional conditions, in particular in the Neutral-Emotional condition. In our work, this enhanced memory is associated with increased hippocampus-amygdala coupling and overall network connectivity. In addition, we show that in the Emotional-Emotional condition, the coupling of the hippocampus and amygdala, as well as the whole network connectivity increases when the first images valence is substantially less negative rated than the second image. This pattern mirrors the Neutral-Emotional condition, where the first image is neutral compared with the second one. Moreover, our model-based analyses suggest that the amygdala predominantly influences the other two regions in the Neutral-Emotional condition, whereas the OFC plays a dominant role in the other two conditions. Combined data-driven modeling, stability analyses, and graph-theory tools led to new insights and enhanced the mechanistic understanding of cortical dynamics of emotional associative memory. We discuss these insights, utilize these analytical tools to generalize our findings to some unmeasured conditions, and highlight the potential of these techniques to inform the design of future regulatory mechanisms.

neuroscience↗

bioRxiv2025

Unraveling the Dual Immunomodulatory and Immunogenic Roles of the Central Conserved Cysteine-Rich Region in Respiratory Syncytial Virus G Protein

Respiratory syncytial virus (RSV) causes severe respiratory disease in infants and high-risk adults, in part by subverting host immunity. The RSV G glycoproteins central conserved cysteine-rich domain (CCD) contains a CX3C motif implicated in immune modulation, but the relationship between CCD redox state, structure and function is unresolved. We recombinantly expressed a CCD peptide (Gpep, residues 149-196) and combined structural and biophysical characterizations with cellular immunology and human serology to define how redox-dependent conformations govern immunogenicity and immunomodulation. Reduced Gpep is compact and rapidly folds via a dominant intermediate into an oxidized, extended monomer; at higher concentrations intermolecular disulfide isomerization produces covalent oligomers. Functionally, monomeric Gpep potently suppresses innate and adaptive activation inhibiting LPS- or UV-inactivated RSV-induced maturation of mouse bone marrow-derived dendritic cells, reducing antigen-specific CD4+ T cell proliferation and IFN-{gamma} production, and attenuating multiple human neutrophil responses (chemotaxis, CD11b upregulation, ROS, MPO release and NET formation), without cytotoxicity. Oligomerized Gpep lacks these suppressive activities. To link molecular mechanism and human exposure, analysis of sera from an ambulatory pediatric cohort (0-72 months) showed a progressive transient increase in the anti-F/anti-G IgG ratio with repeated early RSV exposures, maturating into a functional 2 to 3 ratio. This serologic shift is consistent with previously reported enrichment of F-directed neutralizing immunity. We propose a redox-dependent immune-evasion model in which soluble, monomeric G mediates transient immunosuppression that is removed by disulfide-driven oligomerization, which may occur in membrane-bound G. This may impact therapeutic strategies that commonly favor F-focused responses. ImportanceRespiratory syncytial virus (RSV) remains a leading cause of severe respiratory disease in young children and high-risk adults. This study identifies a chemical switch in a small conserved region of the RSV attachment protein that changes its shape and immune activity: when the region is present as a soluble, single chain, it transiently suppresses key innate and adaptive immune cells, but this activity is lost upon disulfide-mediated oligomerization. We also show that repetitive RSV exposures in early life bias the antibody response, initially boosting antibody responses toward the Fusion protein, rather than this conserved central region. Together, these results may uncover a mechanism by which RSV shapes the host immune response explaining the features of antibody development in children. Understanding this redox-dependent balance between immune evasion and antigenicity will inform safer vaccine and antibody strategies against RSV.

immunology↗

bioRxiv2025

Multi-Omics analyses reveal dynamic interactions between DNA methylation and transcriptional regulation during black raspberry ripening

We profiled developmental-series transcriptome, methylome, and metabolome profiling to reveal extensive epigenetic reprogramming during black raspberry (Rubus occidentalis) fruit ripening. Fruit tissues exhibit globally higher DNA methylation than leaves, particularly in CHG and CHH contexts. Local methylation in all cytosine contexts progressively decreases in promoter regions during ripening, whereas CHG and CHH methylation increase in transposon-rich regions. Two primary methylation transitions--promoter hypomethylation and CHH hypermethylation--govern transcriptional shifts in genes involved in ripening processes. Methyl-binding transcription factors with activation potential likely promote CHH hypermethylation-linked transcriptional activation. Multi-omics integration revealed coordinated anthocyanin accumulation parallels expression of biosynthetic and regulatory genes within coherent networks. Elevated non-CG methylation in heterochromatin coincides with increased transcription of histone variants mediating chromatin compaction, suggesting chromatin remodelers fine-tune accessibility for methyltransferases. Our study highlights both genome-wide and locus-specific epigenetic reprogramming and demonstrates a coordinated interplay between DNA methylation and transcriptional regulation during black raspberry fruit ripening.

genomics↗

bioRxiv2025

The elusive neural signature of emotion regulation capabilities: evidence from a large-scale consortium

Cognitive reappraisal is a fundamental emotion regulation strategy for mental and physical well-being, but how its neural mechanisms relate to individual differences remains poorly understood. In a consortium effort analyzing 40 fMRI datasets (N=2,175), we examined the relationship between neural activation during reappraisal tasks and three core individual difference indices of reappraisal capabilities: (1) trait questionnaires, (2) task-based affective ratings, and (3) amygdala down-regulation. Strikingly, there was no shared overlap across these three common indices. Only a very weak correlation emerged between amygdala down-regulation and task-based affective ratings. Whole-brain analyses revealed no reliable neural associations with trait questionnaires, and associations with task-based affective ratings fell outside canonical emotion regulation networks (e.g., prefrontal circuitry). Moreover, amygdala down-regulation, often interpreted as a stable individual marker, was confounded by person-specific whole-brain responses -- a limitation extending to fMRI research beyond the emotion regulation domain. These findings challenge the assumption that an individuals prefrontal activity is a valid indicator of their reappraisal capabilities and suggest that common trait, behavioral, and neural measures might capture distinct facets of emotion regulation. More broadly, our results highlight concrete methodological challenges for fMRI research on individual differences, with implications extending beyond emotion regulation to the neuroscience of personality, psychopathology, and general well-being.

neuroscience↗

bioRxiv2025

Hippocampal Synchrony Dynamically Gates Cortical Connectivity Across Brain States

Memory consolidation is thought to rely on hippocampo-cortical dialogue orchestrated by three cardinal sleep oscillations: cortical slow oscillations, thalamic spindles, and hippocampal sharp-wave ripples. However, how hippocampal outputs are routed to specific cortical targets and dynamically regulated across brain states remains incompletely understood. Here, we performed simultaneous multisite recordings from the dorsal and ventral hippocampus, and frontal and parietal cortex in rats alternating between wakefulness and sleep. Frontal slow oscillations operated as a global clock, resetting thalamic circuits and initiating spindle volleys that propagated from anterior to posterior cortex, while parietal slow oscillations more effectively recruited hippocampal ripples. Hippocampal ripples reflected anatomical connectivity, as dorsal ripples preferentially enhanced parietal spindles, whereas ventral ripples engaged mainly frontal spindling. Notably, when ripples synchronized in dorsal and ventral hippocampus, local excitatory drive sharply decreased and neuronal spiking redistributed, associated cortical slow oscillations and spindle responses diminished, and cortical neuronal reactivation was suppressed, indicating that dorso-ventral ripple synchrony gates, rather than amplifies, hippocampo-cortical communication. This gating effect was most evident through interactions with brain state, as dorsal-driven reactivation persisted across vigilance states, while ventral pathways were more pronounced during sleep. Collectively, our results outline a multilayer architecture in which slow oscillations provide a global temporal scaffold, spindles implement anatomically specific reactivation channels, and ripple coordination gates hippocampo-cortical communication, likely shaping the precision and specificity of memory consolidation within a highly variable neural substrate. SignificanceSharp-wave ripples in the hippocampus are critical for memory consolidation, in part due to their precise temporal coordination with cortico-thalamic sleep rhythms. However, whether ripple synchronization along the hippocampal septo-temporal axis modulates cortical memory processing has remained unresolved. Here, we show that coordinated ripples, occurring simultaneously in dorsal and ventral CA1, are observed more frequently than predicted by independent occurrence and are associated with significant suppression of cortical reactivation compared to isolated episodes. This suppression does not reflect simple changes in ripple structure or increased inhibition, but instead is linked to a redistribution of excitatory drive across the hippocampal septo-temporal axis. Importantly, this gating effect is present across both sleep and wakefulness. These findings suggest that hippocampal synchrony dynamically gates, rather than amplifies, cortical engagement, thus refining systems consolidation models by highlighting the significance of network organization and precise temporal dynamics in shaping memory replay.

neuroscience↗

bioRxiv2024

Modular Fluorescent Cholesterol Naphthalimide Probes And Their Application For Cholesterol Trafficking Studies In Cells

Development of fluorescent cholesterol analogs to better understand subcellular cholesterol trafficking is of great interest for cell biology and medicine. Our approach utilizes a bifunctional 1,8-naphthalimide scaffold with a push-pull character, modified on one side with a head group and a linker on the other side connecting it to cholesterol via an ester bond. Through structure-function studies, weve explored how different substituents--linkers and head groups--affect the ability of these fluorescent cholesterol naphthalimide analogs (CNDs) to mimic natural cholesterol behavior at both molecular and cellular levels. We categorized the resulting analogs into three groups: neutral, charged, and those featuring a hydroxyl group. Each compound was assessed for its solvatochromic behavior in organic solvents and model membranes. Extensive all-atom molecular dynamics simulations helped us examine how these analogs perform in model membranes compared to cholesterol. Additionally, we investigated the partitioning of these fluorescent probes in phase-separated giant unilamellar vesicles. We evaluated the uptake and distribution of these probes within mouse fibroblast cells and astrocytes, for their subcellular distributions in lysosomes and compared that to BODIPY-cholesterol, a well-regarded fluorescent cholesterol analog. The internalization efficiency of the fluorescent probes varies in different cell types and is affected mainly by the head groups. Our results demonstrate that the modular design significantly simplifies the creation of fluorescent cholesterol probes bearing distinct spectral, biophysical, and cellular targeting features, which makes it a valuable toolkit for the investigation of subcellular distribution and trafficking of cholesterol and its derivatives.

biochemistry↗

bioRxiv2023

Emotional information facilitates or disrupts memory integration through distinct hippocampal processes of reactivation and connectivity

Emotion has a significant impact on how related experiences are organized into integrated memories. However, the neurobiological mechanisms of how emotion modulates memory integration for related information with different valences remain unclear. In this between-subject functional magnetic resonance imaging (fMRI) study, we investigated different emotional modulations of memory integration by manipulating the valence of stimuli used in an associative memory paradigm. Three groups of participants were tested: one group integrated emotional (i.e., negative) information with neutral information, one group integrated two emotional pieces of information, and one control group integrated two neutral pieces of information. Behaviorally, emotional information facilitated its integration with neutral information but interfered with the other emotional information. Neurally, the emotion-induced facilitation effect, occurring on memory integration of neutral and emotional information, was associated with increased trial-specific reactivation in the hippocampus during both encoding and retrieval. This facilitated integration was also supported by strengthened hippocampal connectivity with the amygdala, as well as a set of neocortical areas related to emotion regulation and the default mode network (DMN). In contrast, the emotion-induced interference effect, occurring on memory integration of two emotional pieces of information, was associated with impaired hippocampal trial-specific reactivation during retrieval that appeared to offset the facilitating effect of increased reactivation during encoding. Similar but relatively weak hippocampal connectivity was found underlying this interfered integration. Taken together, emotional information facilitates memory integration with neutral information, while disrupting the integration with other emotional information, through distinct dynamical processes of hippocampal trial-specific reactivation and connectivity.

neuroscience↗

bioRxiv2023

KDM6 demethylases mediate EWSR1-FLI1-driven oncogenic transformation in Ewing Sarcoma

Ewing Sarcoma (EwS) is an aggressive bone and soft tissue tumor driven by the fusion oncoprotein EWSR1-FLI1. This aberrant transcription factor binds to GGAA microsatellites, causing epigenetic reprogramming through the formation of active neo-enhancers in a permissive cellular context. Inhibition of the oncogene remains challenging and current efforts instead seek to exploit emergent epigenetic treatments targeting EWSR1-FLI1 cofactors. Here, stemming from the genome-wide redistribution of H3K27me3 upon expression of EWSR1-FLI1 in pediatric hMSC, we unravel the contribution of the H3K27me3 demethylases KDM6A and KDM6B in transcriptional activation at EWSR1-FLI1 enhancers. We found that KDM6A has a demethylase-independent role in recruiting the SWI/SNF member BRG1 at EWSR1-FLI1-primed enhancers containing single GGAA motif, which is critical for EwS tumor growth. Conversely, KDM6B demethylates H3K27me3 at EWSR1-FLI1-active enhancers containing multimeric GGAA repeats and its deletion synergizes with EZH2 inhibitors. Our results highlight KDM6 demethylases as EWSR1-FLI1 cofactors with potential for future targeted therapies.

cancer biology↗

bioRxiv2022

Effect of intranasal administration of neuroEPO in the histological structure of the olfactory mucosa of rats Wistar

IntroductionStrokes and neurodegenerative diseases are major global health problems. Not only because they cause high mortality and disability, but to the lack of effective therapies. NeuroEPO, a variant of recombinant human erythropoietin (rHu-EPO) with a low sialic acid content, has shown encouraging results as a potential neuroprotective agent when administered intranasally. ObjectiveTo determine the effect of intranasal administration of NeuroEPO on the histological structure of the olfactory mucosa of Wistar rats. Materials and MethodsAn experimental, prospective, and longitudinal study was conducted in Wistar rats. Ten healthy animals were randomly distributed into two groups of five each. The control group received a vehicle (0.3 l/g/day) and the treated group received NeuroEPO (300 g/kg/day). Both treatments were administered intranasally for 28 days. The histological characteristics of the olfactory mucosa were evaluated. The medians of the study groups were compared using the Mann-Whitney U test. ResultsThere were no alterations in the histological characteristics of the olfactory epithelium. However, at the level of the lamina propria in the group treated with NeuroEPO, slight hypertrophy, and hyperplasia of the Bowmans glands was observed. ConclusionsThe administration of the nasal formulation of NeuroEPO did not induce histological alterations of the olfactory mucosa of Wistar rats under the experimental conditions of this research.

pharmacology and toxicology↗

bioRxiv2021

Non-REM sleep in major depressive disorder

Disturbed sleep is a key symptom in major depressive disorder (MDD). REM sleep alterations are well described in the current fliterature, but little is known about non-REM sleep alterations. Additionally, sleep disturbances relate to a variety of cognitive symptoms in MDD, but which features of non-REM sleep EEG contribute to this, remains unknown. We comprehensively analyzed non-REM sleep EEG features in three independently collected datasets (N=284). These included MDD patients with a broad age range, varying duration and severity of depression, unmedicated or medicated, age- and gender-matched to healthy controls. We explored changes in sleep architecture including sleep stages and cycles, spectral power, sleep spindles, slow waves (SW), and SW-spindle coupling. Next, we analyzed the association of these sleep features with acute measures of depression severity and overnight consolidation of procedural memory. Overall, no major systematic alterations in non-REM sleep architecture were found in patients compared to controls. For the microstructure of non-REM sleep, we observed a higher spindle amplitude in unmedicated patients compared to controls, and after the start of antidepressant medication longer SWs with lower amplitude and a more dispersed SW-spindle coupling. In addition, long-term, but not short-term medication seemed to lower spindle density. Overnight procedural memory consolidation was impaired in medicated patients and associated with lower sleep spindle density. Our results suggest that alterations in non-REM sleep EEG might be more subtle than previously reported. We discuss these findings in the context of antidepressant medication intake and age. Statement of SignificanceDepression affects large and diverse populations worldwide, including their sleep. Most sleep is non-REM sleep, which is vital to cognitive function, including memory. How non-REM is affected during a depression or medical treatment remains poorly investigated. We classified non-REM sleep of depressive patients against healthy controls in unprecedented analysis detail and confidence using the largest dataset published so far while also test sleep alterations associations with impaired memory. Surprisingly, severe depression alone did not alter sleep. We observed severe non-REM sleep alterations only worsening under patient medication, which ultimately coincided with 24-hour memory impairments. Though causal influences of medication on sleep in depressive patients remains to be investigated, this cautions common clinical practice in long-term treatment with antidepressants.

neuroscience↗

bioRxiv2021

A New Old Tale: Dopamine Transporter implications in an animal model of Attention-Deficit Hyperactivity Disorder

Attention deficit/Hyperactivity disorder (ADHD) is one of the most diagnosed psychiatric disorders nowadays. The core symptoms of the condition include hyperactivity, impulsiveness and inattention. The main pharmacological treatment consists of psychostimulant drugs affecting Dopamine Transporter (DAT) function. We have previously shown that genetically modified mice lacking p35 protein (p35KO), which have reduced Cdk5 activity, present key hallmarks resembling those described in animal models useful for studying ADHD. The p35KO mouse displays spontaneous hyperactivity and shows a calming effect of methylphenidate or amphetamine treatment. Interestingly, dopaminergic neurotransmission is altered in these mice as they have an increased Dopamine (DA) content together with a low DA turnover. This led us to hypothesize that the lack of Cdk5 activity affects DAT expression and/or function in this animal model. In this study, we performed biochemical assays, cell-based approaches, quantitative fluorescence analysis and functional studies that allowed us to demonstrate that p35KO mice exhibit decreased DA uptake and reduced cell surface DAT expression levels in the striatum (STR). These findings are supported by in vitro observations in which the inhibition of Cdk5 activity in N2a cells induced a significant increase in constitutive DAT endocytosis with a concomitant increase in DAT localization to recycling endosomes. Taken together, these data provide evidences regarding the role of Cdk5/p35 in DAT expression and function, thus contributing to the knowledge of DA neurotransmission physiology and also providing therapeutic options for the treatment of DA pathologies such as ADHD.

neuroscience↗

bioRxiv2020

Brain preparedness: The proactive role of the cortisol awakening response

Upon awakening from nighttime sleep, the stress hormone cortisol exhibits a burst in the morning within 30-minutes in humans. This cortisol awakening response (CAR) is thought to prepare the brain for upcoming challenges. Yet, the neurobiological mechanisms underlying the CAR-mediated preparation function remains unknown. Using blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD-fMRI) with a dedicated prospective design and pharmacological manipulation, we investigated this proactive mechanism in humans across two fMRI studies. In Study 1, we found that a robust CAR was predictive of less hippocampal and prefrontal activity, though enhanced functional coupling between those regions and facilitated working memory performance, during a demanding task later in the afternoon. These results implicate the CAR in proactively promoting brain preparedness based on improved neural efficiency. To address the causality of this proactive effect, we conducted a second study (Study 2) in which we suppressed the CAR with a double blind, placebo controlled, randomized design using Dexamethasone. We found that pharmacological suppression of CAR mirrored the proactive effects from Study 1. Dynamic causal modeling analyses further revealed a reduction of prefrontal top-down modulation over hippocampal activity when performing a cognitively demanding task in the afternoon. These findings establish a causal link between the CAR and its proactive role in optimizing brain functional networks involved in neuroendocrine control and memory.

neuroscience↗

bioRxiv2020

Emotional tagging retroactively promotes memory integration through rapid neural reactivation and reorganization

Neutral events preceding emotional experiences are thought to be better remembered by tagging them as significant to simulate future event predictions. Yet, the neurobiological mechanisms how emotion transforms initially mundane events into strong memories remain unclear. By two behavioral and one fMRI studies with adapted sensory preconditioning paradigm, we show rapid neural reactivation and reorganization underlying emotion-tagged retroactive memory enhancement. Behaviorally, emotional tagging enhanced initial memory for neutral associations across the three studies. Neurally, emotional tagging potentiated reactivation of overlapping neural traces in the hippocampus and stimulus-relevant neocortex. Moreover, it induced large-scale hippocampal-neocortical reorganization supporting such retroactive benefit, as characterized by enhanced hippocampal-neocortical coupling modulated by the amygdala during online processing, and a shift from stimulus-relevant neocortex to transmodal prefrontal-parietal areas during offline post-tagging rest. Together, emotional tagging retroactively promotes associations between past neutral events through stimulating rapid reactivation of overlapping representations and reorganizing related memories into an integrated network.

neuroscience↗

bioRxiv2020

The dynamic transition between neural states is associated with the flexible use of memory

Flexible behavior requires switching between different task conditions. It is known that such task- switching is associated with costs in terms of slowed reaction time, reduced accuracy, or both. The neural correlates of task-switching have usually been studied by requiring participants to switch between distinct task demands that recruit different brain networks. Here, we investigated the transition of neural states underlying switching between two opposite memory-related processes (i.e., memory retrieval and memory suppression) in a memory task. We investigated 26 healthy participants who performed a Think/No-Think task while being in the fMRI scanner. Behaviorally, we show that it was more difficult for participants to suppress unwanted memories when a No-Think was preceded by a Think trial instead of another No- Think trial. Neurally, we demonstrate that Think-to-No-Think switches were associated with an increase in control-related and a decrease in memory-related brain activity. Neural representations of task demand, assessed by decoding accuracy, were lower immediately after task switching compared to the non-switch transitions, suggesting a switch-induced delay in the neural transition towards the required task condition. This suggestion is corroborated by an association between condition-specific representational strength and condition-specific performance in switch trials. Taken together, we provided neural evidence from the time-resolved decoding approach to support the notion that carry-over of the previous task-set activation is associated with the switching cost leading to less successful memory suppression. Significance statementOur brain can switch between multiple tasks but at the cost of less optimal performance during transition. One possible neuroscientific explanation is that the representation of the task condition is not easy to be updated immediately after switching. Thus, weak representations for the task at hand explain performance costs. To test this, we applied brain decoding approaches to human fMRI data when participants switched between successive trials of memory retrieval and suppression. We found that switching leads to a weaker representation of the current task. The remaining representation of the previous, opposite task is associated with inferior performance in the current task. Therefore, timely updating of task representations is critical for task switching in the service of flexible behaviors.

neuroscience↗

bioRxiv2020

Overlapping connectivity gradients in the anterior temporal lobe underlie semantic cognition

Convergent evidence from neuroimaging, computational, and clinical research has shown that the anterior temporal lobe (ATL) is critically involved in two key aspects of semantic cognition: the representation of semantic knowledge, and the executive regulation of this knowledge. Both are necessary for integrating features to understand concepts, and to integrate concepts to understand discourse. Here, we tested the hypothesis that these differential aspects of integration map onto different patterns of ATL connectivity. Specifically, we hypothesized that there are two overlapping modes of functional connectivity of the ATL that each predict distinct aspects of semantic cognition on an individual level. We used a novel analytical approach (connectopic mapping) to identify the first two dominant modes connection topographies (i.e. maps of spatially varying connectivity) in the ATL in 766 participants (Human Connectome Project), and summarized these into 16 parameters that reflect inter-individual differences in their functional organization. If these connection topographies reflect the ATLs functional multiplicity, then we would expect to find a dissociation where one mode (but not the other) correlates with cross-modal matching of verbal and visual information (picture vocabulary naming), and the other (but not the former) correlates with how quickly and accurately relevant semantic information is retrieved (story comprehension). Our analysis revealed a gradient of spatially varying connectivity along the inferior-superior axis, and secondly, an anterior to posterior gradient. Multiple regression analyses revealed a double dissociation such that individual differences in the inferior-superior gradient are predictive of differences in story comprehension, whereas the anterior-posterior gradient maps onto differences in picture vocabulary naming, but not vice versa. These findings indicate that overlapping gradients of functional connectivity in the ATL are related to differential behaviors, which is important for understanding how its functional organization underlies its multiple functions.

neuroscience↗

bioRxiv2020

Durable memories and efficient neural coding through mnemonic training using the method of loci

Mnemonic techniques, such as the method of loci, can powerfully boost memory. Here, we compared memory athletes ranked among the worlds top 50 in memory sports to mnemonics-naive controls. In a second study, participants completed a six-weeks memory training, working memory training, or no intervention. Behaviorally, memory training enhanced durable, longer-lasting memories. fMRI during encoding and recognition revealed task-based activation decreases in lateral prefrontal, as well as in parahippocampal and retrosplenial cortices in both memory athletes and participants after memory training, partly associated with better performance after four months. This was complemented by hippocampal-neocortical coupling during consolidation, which was stronger the more durable memories participants formed. Our findings are the first to demonstrate that mnemonic training boosts durable memory formation via decreased task-based activation and increased consolidation thereafter. This is in line with conceptual accounts of neural efficiency and highlights a complex interplay of neural processes critical for extraordinary memory.

neuroscience↗

bioRxiv2020

HUMAN PANCREATIC CANCER CELLS UNDERGO PROFOUND METABOLIC REPROGRAMMING TOWARDS CELLULAR STEMNESS AS ADAPTATION TO INHIBITION OF THE AKT PATHWAY

Cancer cells acquire resistance to cytotoxic therapies targeting major survival pathways by adapting their metabolism. The AKT pathway is a major regulator of human pancreatic adenocarcinoma progression. The mechanisms of adaptation to long-term silencing of AKT isoforms of pancreatic cancer cells were studied. Following silencing, cancer cells remained quiescent for long periods of time, after which they recovered proliferative capacities. Adaptation caused profound proteomic changes largely affecting mitochondrial biogenesis, energy metabolism, and acquisition of a number of distinct cancer stem cell (CSC) characteristics depending on the AKT isoform that was silenced. The adaptation to AKT1 silencing drove most de-differentiation and acquisition of stemness through C-MYC down-modulation and NANOG up-regulation, which were required for survival of adapted CSCs. The changes associated to adaptation sensitized cancer cells to inhibitors targeting regulators of oxidative respiration and mitochondrial biogenesis. In vivo pharmacological co-inhibition of AKT and mitochondrial metabolism effectively controlled pancreatic adenocarcinoma growth in pre-clinical models.

cancer biology↗